atent office



Patented Apr. 26, 1949 units STATES PATENT OFFICE PROPYLENE GLYCQL SOLUTIONS OF DIHYDROXY lETHERS No Drawing. Application August 28, 1946, Serial 2 Claims.

This invention is for improvements in or relating to ethers and has particular reference to a process for increasing the water-solubility of aryl Bry-dihydroxyprcpyl ethers, e. g. phenyl Bil dihydroxypropyl ether and their nuclear-substituted derivatives.

Phenyl fiz- -dihydroxypropyl ether and certain of its nuclear-substituted derivatives and ring homologues have a value as therapeutic agents but this value is limited by their relatively slight solubility in Water. Thus, p-chlorophenyl fli'ydihydroirypropyl ether is only soluble in water to an extent of less than 1% at room temperature while o-tolyl cw-dihydrcxypropyl ether is soluble to an extent less than about 2.0% at room temperature. An increase in the solubility of such fiz'y-dihydroxypropyl ethers is very desirable and it is an object of the present invention to effect such increase in the water-solubility, particularly with a view to extending their therapeutic use.

We have now found that the solubility in Water of phenyl fiz' -dihydroxypropyl ether and of its nuclear-substituted derivatives and in particular of p-chlorophenyl pz' -dihydroxypropyl ether and of o-tolyl flw-dihydroxypropyl ether may be markedly increased in the presence of ethyl urea or propylene glycol (clihydroxypropane consisting substantially of 1 2-dihydroxypropane) According to the present invention, a process for increasing the Water-solubility of aryl 5:7- dihydroxypropyl ethers and particularly of pchlorophenyl fkY-dihydroxypropyl ether and otolyl cw-dihydroxypropyl ether comprises associating with the ether a proportion of ethyl urea of propylene glycol or of a mixture of these two substances. The ether may be incorporated with the ethyl urea or propylene glycol and the mixture subsequently dissolved in Water or the ether may be dissolved in an aqueous solution of the ethyl urea or propylene glycol,

The present invention may be carried into effeet by any one of the following methods. The solution of the ether in aqueous propylene glycol may be prepared at a temperature higher than room temperature and the solution then allowed to cool. Alternatively, the propylene glycol may be heated with the ether and water may be added at any subsequent stage of the preparation of the solution. Again, the ether may be heated with a portion of the glycol and the remainder of the glycol and the water may subsequently be added either together or the glycol may be added followed by water. In a further method, the fli'y-dihydroxypropyl ether may be heated slightly above its melting point and then i in Great Britain June 28, 1946 added to the propylene glycol, water being subsequently added to the mixture. In the case of o-tolyl firy-dihydroxypropyl ether (M. P. 68 to 70 C.) the temperature may with advantage be raised to C.

Of these methods, the last two are particularly advantageous when employed in large scale practice.

It has been found that by use of the present invention, the water-solubility of p-chlorophenyl ,Bw-dihydroxypropyl ether and of o--tolyl pzydihydroxypropyl ether may be increased to a value of the order of 10%, a result not to be anticipated from the properties of the ethers or of ethyl urea or propylene glycol. Further, the increase in Water-solubility is accompanied by an improvement in certain of the therapeutic properties, for example, the antibacterial properties of the ethers over and above the improvement associated with the solubility increase.

Following is a description by way of example of methods of carrying the invention into efi'ect:

Example I The solubility of o-tolyl pz'y-dihydroxypropyl ether in Water at room temperature does not exceed 2%. When this ether is dissolved in water containing 8% by weight of ethyl urea a solution containing 3.2 g. of the ether per ml. of solution may be obtained. Similarly, when the ether is dissolved in water containing 16% by weight of ethyl urea, a solution containing 6.4 g. of the ether per 100 ml. of solution may be obtained. Again, when the ether is dissolved in water containing 32% by weight of ethyl urea, a solution containing 12.8 g. of the ether per 100 ml. of solution may be obtained.

Erample II Percent by g. ether per weight of 100 ml. of ethyl urea of solution Example III The solubility of o-tolyl cw-dihydroxypropyl Volume1 of propy eneg yco per Temperag. other per 100 2%; ga g? 9 ture range, ml. of aqueous pylene glycol C. propylene glycol solution 15 21 to 24 1.5120 1.7 30 21 t0 25 2. 6 to 2.8 40 24 t0 28 6.6 to 7.

It has been found that stable supersaturated solutions of the o-tolyl ether in aqueous propylene glycol can be obtained by preparing a solution at a temperature above room temperature and subsequently cooling to room temperature. Thus, a solution containing g. of the o-tolyl ether in 100 ml. of aqueous propylene glycol containing 20 volumes of propylene glycol in 100 volumes of the aqueous propylene glycol solution prepared at a higher temperature and then allowed to cool to 20 C. may remain clear for at least several days.

We claim:

1. An aqueous-propylene glycol solution containing a therapeutically effective concentration of an ether selected from the group consisting of tolyl-p 'y-dihydroxypropyl and chlorphenyl-fl 'ydihydroxyprop-yl ethers, said solution containing a major proportion of water and a minor proportion of propylene glycol.

2. An aqueous-propylene glycol solution containing a therapeutically effective concentration up to 10% of an ether selected from the group consisting of tolyl-Br'y-dihydroxypropyl and chlorphenyl-fi:v-dihydroxypropyl ethers, said solution containing a major proportion of water and a minor proportion of propylene glycol.

FRANK MILAN BERGER. WILLIAM BRADLEY. FREDERICK GEORGE SAYER.

REFERENCES CITED The following references are of record in the file of this patent:

UNITED STATES PATENTS Number Name Date 2,075,018 Bruson et a1 Mar. 30, 1937 FOREIGN PATENTS Number Country Date 277,003 Great Britain May 17, 1928 OTHER REFERENCES J. A. P. A., Prac. Pharm. Ed., June 1943, pages 194-195.

Coblentz: The Newer Remedies, 3rd ed., 1899, page 68.

Hartman et al.: American Journal of Surgery, Dec. 1939, pages 460-467.

Remington et al.: Practice of Pharmacy, 5th ed, J. B. Lippincott, 1907, pages 306, 308, 731.

Kamm: Qualitative Organic Analysis, John Wiley 8; Sons, Inc., pages 8-10.

Meleny: Report of May 15, 1945, to Committee on Medical Research of the Office of Scientific Research and Development, Report No. 12. Contract OEMcmr-334. 4 pages. Unclassified.

Zirkovic: Monatshefte, vol. 29 (1908), pages 952-958. 

